Dexchlorpheniramine is the dextrorotary isomer of chlorpheniramine, a well-known antihistamine that is a racemic mixture of the dextrorotary and the levorotary isomers. The dextrorotary isomer is the isomer that is active in the mammalian body. Chlorpheniramine in the form of the free base is an oily liquid having a boiling point of 142° C. at 1.0 mm Hg. The dextrorotary isomer of chlorpheniramine has an optical rotation of [α]D25+49.8° (c=1 in dimethylformamide). U.S. Pat. No. 3,061,517 discloses the resolution of the pharmacologically active d-isomer from the chlorpheniramine racemate by treating the racemate with an optically active d- or 1-isomer of a substituted succinic acid
Chlorpheniramine maleate is a crystalline solid having a melting point of 130-135° C. The dextrorotary isomer of chlorpheniramine maleate is also known—it is a crystalline solid having a melting point of 113-115° C. and an optical rotation of [α]D25+44.3° (c=1 in dimethylformamide) and is prepared by reacting a stoichiometric amount of the dextrorotary isomer with maleic acid.
Chlorpheniramine in the form of its free base, including its dextrorotary isomeric form, is somewhat unstable and it is insoluble in water. Accordingly, chlorpheniramine as well as dexchlorpheniramine, is utilized typically in the form of its maleate or hydrobromide monohydrate salt which is soluble in water.
Chlorpheniramine finds its principal use as an antihistamine. It is typically administered to human beings in need of such medication in the form of tablets and/or suspensions. It frequently is administered as an antihistamine/antitussive composition consisting of chlorpheniramine maleate/dextromethorphan hydrobromide monohydrate.
The currently administered forms of chlorpheniramine and dexchlorpheniramine, i.e., generally the maleate or the hydrobromide monohydrate salts, are disadvantageous in that they are absorbed very quickly in the mammalian body. Accordingly, although such forms provide prompt relief, multiple doses must be taken on a daily basis to provide an effective level of medicament over the prescribed period of treatment (generally several days to one week). Until recently, the only slow-release forms of chlorpheniramine that were available were those such as polymer-coated tablets Such prior art formulations provided mixed results in that the chlorpheniramine was not available for adsorption into the patient's bloodstream until the polymeric coating was dissolved, but thereafter the chlorpheniramine was quickly absorbed and metabolized. The result is that frequently, the chlorpheniramine had to again be administered to the patient within the period of only a few hours.
The foregoing problem was solved by converting the chlorpheniramine free base into its tannate salt by reaction of the free base with tannic acid. The tannate salt stabilizes the chlorpheniramine free base and most importantly, imparts extended release properties to the chlorpheniramine. In recent years, tannate salts of antihistamines such as chlorpheniramine have become known, e.g., see U.S. Pat. Nos. 5,599,846; 5,663,415; 6,037,358; 6,287,597; and 6,306,904.
Dexchlor tannate has not been heretofore known in the prior art. Perhaps those skilled in the art felt that the dexchlorpheniramine free base if converted into a salt other than its maleate would undergo racemization to the mixture of the dextro and levo isomers. Since it is only the dextro isomer that is active in the mammalian body, it would, of course, be desirable to administer the dextro isomer rather than the racemate. The prior art has achieved such desirable result by utilizing the dextro isomer in the form of the maleate salt, but dexchlor maleate does not have desirable extended-release properties.
It has now been found that by the hot melt method of this invention, it is possible to convert dexchlorpheniramine into dexchlor tannate and unexpectedly, the dexchlorpheniramine does not undergo racemization in the course of its conversion to the tannate. This was quite surprising since a similarly useful antihistamine, e.g., levo-phenylephrine, undergoes racemization when it is reacted with tannic acid by the hot melt method of the invention.